The polysaccharide chitosan is the at least partially N-deacetylated derivative of chitin. Chitin can be found widely in the exoskeletons of arthropods, gels, crustaceans and the cuticles of insects. It is usually derived from such natural sources. Chitosan in general is synthetically prepared by hydrolysis of chitin, although it can also be naturally derived directly, e.g. from certain fungi in which it occurs. The different solubilities of chitin and chitosan in dilute acids are commonly used to distinguish between the two polysaccharides. Chitosan, the soluble form, can have a degree of acetylation (DA) between 0% and about 60%, the upper limit depending on parameters such as processing conditions, molecular weight, and solvent characteristics. While soluble in acidic aqueous media, chitosan precipitates at a pH of above 6.3.
Both chitin and chitosan are promising polymers for biomedical applications because of their biocompatibility, biodegradability and structural similarity to the glycosaminoglycans. For comprehensive reviews of potential applications of chitin and chitosan see, e.g., Shigemasa and Minami, “Applications of chitin and chitosan for biomaterials”, Biotech. Genetic. Eng. Rev. 1996, 13, 383; Kumar, “A review of chitin and chitosan applications”, React. Funct. Polym. 2000, 46(1), 1; and Singh and Ray, “Biomedical applications of chitin, chitosan and their derivatives”, J. Macromol. Sci. 2000, C40(1), 69.
Chitin and chitosan have been held to be of particular promise in wound healing applications, early scientific reports on this subject dating back to 1970 when Prudden et. al. in “The discovery of a potent pure chemical wound-healing accelerator”, Am. J. Surg. 1970, 119, 560 described the successful application of chitin powder on human wounds. The primary factor in the acceleration of wound healing was reported to be the presence of N-acetyl-D-glucosamine (in contrast to D-glucosamine) which is released from chitin due to enzymatic degradation by lysozyme, which is abundantly available in fresh and healing wounds.
The use of poly(N-acetyl-D-glucosamine), i.e. chitin, as a wound healing accelerator is disclosed in the U.S. Pat. No. 3,632,754. U.S. Pat. No. 4,532,134 discloses the application of chitosan solutions, powders, films, and mats to wounds. The claimed method asks for chitosan being between 42 to 100% deacetylated. Animal experiments using 78 to 92% deacetylated chitosan are disclosed that show acceptable results when the material is applied to wounds of dogs, while interference with early wound healing is observed when the material is used to cover wounds of rats.
In the U.S. Pat. No. 5,902,798 and the US patent application US 2001/0056079 degrees of acetylation of less than 25% are asked for. In experiments applying 16% acetylated chitosan, inferior stimulation of cell proliferation and wound healing were found in an in vitro model using human skin compared to chitosan/heparin materials.
The UK patent GB 2358354 B teaches a flexible polymeric film comprising at least 80% by weight of chitosan with a degree of acetylation between 12 and 30%. A slightly higher rate of wound healing compared to non-treated wounds was found. The relatively weak mechanical properties which necessitate the use of an epichlorhydrine cross-linker or silicon coating may constitute a disadvantage of this prior art material. The document also suggests washing off the film in saline solution after healing of the wound.
Azad et. al., “Chitosan membranes as a wound-healing dressing: Characterization and clinical application”, J. Biomed. Mater. Res. 2004, 69B, 216, discloses the use of 25% acetylated chitosan for the fabrication of films and meshes (perforated films). The authors found that chitosan films cause an impaired wound healing in patients undergoing skin grafting as a result of blood clot formation underneath the film, while the use of meshes led to a more efficient removal of blood, resulting in faster healing with good epithelialization and without scar formation.
In the U.S. Pat. No. 7,482,503 a chitosan acetate foam is described for use as a hemorrhage control wound dressing for severe bleeding. The chitosan is required to be at least 70% deacetylated and in the examples, degrees of deacetylation between 85 and 93% are used.
The US patent application US 2005/042265 A1 discloses a hydrogel for skin repair, the hydrogel containing a maximum of 5% chitosan. The chitosan's degree of acetylation is required to be no greater than 40%, in particular between 2% and 6%. Finally, the international patent application WO 2008/128567 A1 discloses medical articles, including wound dressings, at least partially made of chitosan. The lowest degree of acetylation disclosed is 3%.
The German patent application DE 10 2007 038 125 A1 discloses an adhesive composition for gluing or fixing biological tissue. The composition comprises a 50 to 98% deacetylated polysaccharide, e.g. chitosan. Another component of the composition is a functionalized oligolacton. The two components are provided into separate chambers of a spraying apparatus.
The International patent application WO 2008/1128567 discloses the biodissolution of least a part of a medical device in a dilute acid. The part of the device is made of N-acetylchitosan with a degree of acetylation of more than 3% and less than 25%. The biodissolution of the part of the device is controlled by adjusting the pH of the aqueous medium in contact with the N-acetylchitosan part of the device to a value of equal or less than 6.0.